High plasma efavirenz level and CYP2B66 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: A prospective cohort study

Pharmacogenomics Journal

Volumn 12, Issue 6, 2012, Pages 499-506

  Yimer, G ^a,b   Amogne, W ^a,b   Habtewold, A ^a,b   Makonnen, E ^b   Ueda, N ^a   Suda, A ^a   Worku, A ^b   Haefeli, W E ^c   Burhenne, J ^c   Aderaye, G ^b   Lindquist, L ^a   Aklillu, E ^a  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^b ADDIS ABABA UNIVERSITY   (Ethiopia)

^c UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

antiretroviral; CYP2B6; Efavirenz; ethiopians; hepatotoxicity; HIV

Indexed keywords

ALANINE AMINOTRANSFERASE; ALBUMIN; ALKALINE PHOSPHATASE; ANTIRETROVIRUS AGENT; ASPARTATE AMINOTRANSFERASE; CYTOCHROME P450 2B6; EFAVIRENZ; EFAVIRENZ PLUS LAMIVUDINE PLUS ZIDOVUDINE; HEPATITIS B SURFACE ANTIGEN; HEPATITIS C ANTIBODY; LAMIVUDINE PLUS STAVUDINE; LAMIVUDINE PLUS TENOFOVIR DISOPROXIL;

ABCB1 GENE; ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALBUMIN BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CD4 LYMPHOCYTE COUNT; CHEMICAL ANALYSIS; CLINICAL EVALUATION; COHORT ANALYSIS; CONTROLLED STUDY; CYP2B6 6 GENE; CYP2B6 GENE; CYP3A5 GENE; DISEASE ASSOCIATION; DISEASE SEVERITY; DRUG BLOOD LEVEL; EARLY DIAGNOSIS; ETHIOPIA; FEMALE; GENE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC MARKER; GENOTYPE; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIVER FUNCTION TEST; MAJOR CLINICAL STUDY; MALE; PHARMACOGENETICS; PREDICTOR VARIABLE; PRIORITY JOURNAL; PROSPECTIVE STUDY; PROTEIN BLOOD LEVEL; THROMBOCYTE COUNT; TOXIC HEPATITIS; TREATMENT DURATION; TREATMENT RESPONSE; UGT2B7 2 GENE; VIRUS LOAD;

ADULT; ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; ARYL HYDROCARBON HYDROXYLASES; BENZOXAZINES; COHORT STUDIES; CYTOCHROME P-450 CYP3A; DRUG-INDUCED LIVER INJURY; FEMALE; GENOTYPE; HIV INFECTIONS; HUMANS; MALE; OXIDOREDUCTASES, N-DEMETHYLATING; P-GLYCOPROTEIN; PROPORTIONAL HAZARDS MODELS; PROSPECTIVE STUDIES;

EID: 84870052832     PISSN: 1470269X     EISSN: 14731150     Source Type: Journal    
DOI: 10.1038/tpj.2011.34     Document Type: Article

References (43)

1. Walker UA. Antiretroviral therapy-induced liver alterations. Curr Opin HIV AIDS 2007; 2: 293-298.
2. Reisler RB, Han C, Burman WJ, Tedaldi EM, Neaton JD. Grade 4 events are as important as AIDS events in the era of HAART. J Acquir Immune Defic Syndr 2003; 34: 379-386.
3. Hernandez LV, Gilson I, Jacobson J, Affi A, Puetz TR, Dindzans VJ. Antiretroviral hepatotoxicity in human immunodeficiency virus-infected patients. Aliment Pharmacol Ther 2001; 15: 1627-1632.
4. Hoffmann CJ, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL et al. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21: 1301-1308.
5. Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis 2003; 23: 173-182.
6. Nunez M, Soriano V. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. Drug Saf 2005; 28: 53-66.
7. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004; 18: 2277-2284.
8. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: 182-189.
9. Martin-Carbonero L, Nunez M, Gonzalez-Lahoz J, Soriano V. Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clin Trials 2003; 4: 115-120.
10. Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K et al. Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics 2007; 8: 547-558.
11. Kwara A, Lartey M, Sagoe KW, Kenu E, Court MH. CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients. AIDS 2009; 23: 2101-2106.
12. Mukonzo JK, Roshammar D, Waako P, Andersson M, Fukasawa T, Milani L et al. A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans. Br J Clin Pharmacol 2009; 68: 690-699.
13. Elens L, Vandercam B, Yombi JC, Lison D, Wallemacq P, Haufroid V. Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients. Pharmacogenomics 2010; 11: 1223-1234.
14. Burger D, van der Heiden I, la Porte C, van der Ende M, Groeneveld P, Richter C et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006; 61: 148-154.
15. Lindfelt T, O0Brien J, Song JC, Patel R, Winslow DL. Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms. Ann Pharmacother 2010; 44: 1572-1578.
16. Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA et al. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis 2010; 202: 717-722.
17. Carr DF, la Porte CJ, Pirmohamed M, Owen A, Cortes CP. Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. J Antimicrob Chemother 2010; 65: 1889-1893.
18. Verdon R, Six M, Rousselot P, Bazin C. Efavirenz-induced acute eosinophilic hepatitis. J Hepatol 2001; 34: 783-785.
19. Hoffmann CJ, Fielding KL, Charalambous S, Sulkowski MS, Innes C, Thio CL et al. Antiretroviral therapy using zidovudine, lamivudine, and efavirenz in South Africa: tolerability and clinical events. AIDS 2008; 22: 67-74.
20. Bruck S, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M et al. Hepatotoxicity in patients prescribed efavirenz or nevirapine. Eur J Med Res 2008; 13: 343-348.
21. Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005; 191: 825-829.
22. Ocama P, Castelnuovo B, Kamya MR, Kirk GD, Reynolds SJ, Kiragga A et al. Low frequency of liver enzyme elevation in HIV-infected patients attending a large urban treatment centre in Uganda. Int J STD AIDS 2010; 21: 553-557.
23. UNAIDS. 2008 Report on the Global AIDS Epidemic. UNAIDS: Geneva, Switzerland, 2008.
24. The Ministry of Health (MOH), HIV/AIDS Prevention Control Office (HAPCO). Aids in Ethiopia 6th report (http://www.etharc.org/aidsineth/publications/ Factsheetfor6threport.pdf), accessed August 2011.
25. Ngaimisi E, Mugusi S, Minzi OM, Sasi P, Riedel KD, Suda A et al. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharmacol Ther 2010; 88: 676-684.
26. Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11: 272-276.
27. Torti C, Lapadula G, Casari S, Puoti M, Nelson M, Quiros-Roldan E et al. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort. BMC Infect Dis 2005; 5: 58.
28. Shipton LK, Wester CW, Stock S, Ndwapi N, Gaolathe T, Thior I et al. Safety and efficacy of nevirapine-and efavirenz-based antiretroviral treatment in adults treated for TB-HIV co-infection in Botswana. Int J Tuberc Lung Dis 2009; 13: 360-366.
29. Servoss JC, Kitch DW, Andersen JW, Reisler RB, Chung RT, Robbins GK. Predictors of antiretroviral-related hepatotoxicity in the adult AIDS Clinical Trial Group (1989-1999). J Acquir Immune Defic Syndr 2006; 43: 320-323.
30. Montessori V, Harris M, Montaner JS. Hepatotoxicity of nucleoside reverse transcriptase inhibitors. Semin Liver Dis 2003; 23: 167-172.
31. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. Aids 2001; 15: 71-75.
32. Gazzard B, Balkin A, Hill A. Analysis of neuropsychiatric adverse events during clinical trials of efavirenz in antiretroviral-naive patients: a systematic review. AIDS Rev 2010; 12: 67-75.
33. Gounden V, van Niekerk C, Snyman T, George JA. Presence of the CYP2B6 516G4 T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIVinfected patients. AIDS Res Ther 2010; 7: 32.
34. Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005; 10: 489-498.
35. Saitoh A, Fletcher CV, Brundage R, Alvero C, Fenton T, Hsia K et al. Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J Acquir Immune Defic Syndr 2007; 45: 280-285.
36. Apostolova N, Gomez-Sucerquia LJ, Moran A, Alvarez A, Blas-Garcia A, Esplugues JV. Enhanced oxidative stress and increased mitochondrial mass during efavirenz-induced apoptosis in human hepatic cells. Br J Pharmacol 2010; 160: 2069-2084.
37. Abrescia N, D0Abbraccio M, Figoni M, Busto A, Butrico E, De Marco M et al. Fulminant hepatic failure after the start of an efavirenzbased HAART regimen in a treatment-naive female AIDS patient without hepatitis virus co-infection. J Antimicrob Chemother 2002; 50: 763-765.
38. Turkova A, Ball C, Gilmour-White S, Rela M, Mieli-Vergani G. A paediatric case of acute liver failure associated with efavirenz-based highly active antiretroviral therapy and effective use of raltegravir in combination antiretroviral treatment after liver transplantation. J Antimicrob Chemother 2009; 63: 623-625.
39. Figueroa SC, de Gatta MF, Garcia LH, Hurle AD, Bernal CB, Correa RS et al. The convergence of therapeutic drug monitoring and pharmacogenetic testing to optimize efavirenz therapy. Ther Drug Monit 2010; 32: 579-585.
40. Nunez MJ, Martin-Carbonero L, Moreno V, Valencia E, Garcia-Samaniego J, Castillo JG et al. Impact of antiretroviral treatment-related toxicities on hospital admissions in HIV-infected patients. AIDS Res Hum Retroviruses 2006; 22: 825-829.
41. Aklillu E, Dandara C, Bertilsson L, Masimirembwa C. Pharmacogenetics of cytochrome P450s in African populations: clinical and molecular evolutionary implications. In: Suarez-Kurtz G (ed). Pharmacogenomics in Admixed Populations. Austin, TX: Landes Bioscience, 2007, pp 99-119.
42. Gebeyehu E, Engidawork E, Bijnsdorp A, Aminy A, Diczfalusy U, Aklillu E. Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians. Pharmacogenomics J 2011; 11: 130-137.
43. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441-446.